In this competing renewal application (currently in its 14th year) we propose to explore the behavioral correlates of polydrug abuse in male and female adult and adolescent subjects by expanding upon our findings during the previous four years of funding. Further, we will continue to focus on changing trends in polydrug abuse, the most recent of which involves the club drug MDMA. The proposed series of experiments are connected via three major inter related themes: I) The neurobiological bases of polydrug abuse will be explored using cue-induced craving and functional magnetic resonance imaging (fMRI). Regional brain activation after exposure to cues from different modalities and drug classes will be assessed using a 4 Tesla magnet that improves spatial resolution and reveals individual differences. The activation profile of exposure to different cues in polydrug abusers will help determine whether there is significant cross-generalization among cues. II) Differences between adolescent and adult polydrug use will be measured using EEG mapping, physiology and behavioral indices during cue-induced craving procedures. As the rate of both tobacco and marihuana smoking among adolescents continues to rise, we will explore the relationship between these two drugs and the generalizability of drug-related cues in adolescents. III) Novel pharmacotherapies for polydrug abuse will be tested as traditional medication trials have focused on testing a single treatment drug. We will use new strategy of combining two medications (polypharmacy) to address the multi-faceted nature of polydrug abuse. Nicotine and selegilinepatches for combined cocaine/tobacco abuse and gabapentin for combined cocaine/alcohol abuse will be studied. A new direction for our laboratory is to study drug-taking behavior in the natural fieldenvironment using a unique wrist actigraphy and data input device to monitor sleep/wake activity, MDMA craving and actual polydrug use while subjects continue with their usual daily routines. Finally, we will explore the impact that the availability of MDMA has on alcohol and marihuana use in a Natural Setting Laboratory. The proposed studies will fill important gaps in our understanding of polydrug abuse including: cue-induced craving in adolescents, actual polydrug patterns, sex-related differences, brain sites associated with craving, similarities among cues, and how best to design effective pharmacotherapies for polydrug abuse. Results of these studies may also reveal why cue-induced craving has not been a good predictor of relapse as there may be significant cross generalization among the cues that can trigger relapse in successfully treated patients.